Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTK0ZN7Y)

• DOT Name: Lys-63-specific deubiquitinase BRCC36 (BRCC3)
• Synonyms: EC 3.4.19.-; BRCA1-A complex subunit BRCC36; BRCA1/BRCA2-containing complex subunit 3; BRCA1/BRCA2-containing complex subunit 36; BRISC complex subunit BRCC36
• Gene Name: BRCC3
• Related Disease:
  Adult glioblastoma
  Cervical cancer
  Cervical carcinoma
  Childhood myelodysplastic syndrome
  Cytomegalovirus infection
  Glioblastoma multiforme
  Glioma
  Myelodysplastic syndrome
  Myelodysplastic/myeloproliferative neoplasm
  Neoplasm
  Osteoporosis
  Parkinson disease
  Severe hemophilia A
  Triple negative breast cancer
  Vascular disease
  Venous thromboembolism
  Nasopharyngeal carcinoma
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Keratoconjunctivitis sicca
  Moyamoya disease
• UniProt ID: BRCC3_HUMAN
• PDB ID: 6H3C; 6R8F
• EC Number: 3.4.19.-
• Pfam ID: PF18110 ; PF01398
• Sequence:
  MAVQVVQAVQAVHLESDAFLVCLNHALSTEKEEVMGLCIGELNDDTRSDSKFAYTGTEMR
  TVAEKVDAVRIVHIHSVIILRRSDKRKDRVEISPEQLSAASTEAERLAELTGRPMRVVGW
  YHSHPHITVWPSHVDVRTQAMYQMMDQGFVGLIFSCFIEDKNTKTGRVLYTCFQSIQAQK
  SSESLHGPRDFWSSSQHISIEGQKEEERYERIEIPIHIVPHVTIGKVCLESAVELPKILC
  QEEQDAYRRIHSLTHLDSVTKIHNGSVFTKNLCSQMSAVSGPLLQWLEDRLEQNQQHLQE
  LQQEKEELMQELSSLE
• Function: Metalloprotease that specifically cleaves 'Lys-63'-linked polyubiquitin chains. Does not have activity toward 'Lys-48'-linked polyubiquitin chains. Component of the BRCA1-A complex, a complex that specifically recognizes 'Lys-63'-linked ubiquitinated histones H2A and H2AX at DNA lesions sites, leading to target the BRCA1-BARD1 heterodimer to sites of DNA damage at double-strand breaks (DSBs). In the BRCA1-A complex, it specifically removes 'Lys-63'-linked ubiquitin on histones H2A and H2AX, antagonizing the RNF8-dependent ubiquitination at double-strand breaks (DSBs). Catalytic subunit of the BRISC complex, a multiprotein complex that specifically cleaves 'Lys-63'-linked ubiquitin in various substrates. Mediates the specific 'Lys-63'-specific deubiquitination associated with the COP9 signalosome complex (CSN), via the interaction of the BRISC complex with the CSN complex. The BRISC complex is required for normal mitotic spindle assembly and microtubule attachment to kinetochores via its role in deubiquitinating NUMA1. Plays a role in interferon signaling via its role in the deubiquitination of the interferon receptor IFNAR1; deubiquitination increases IFNAR1 activity by enhancing its stability and cell surface expression. Acts as a regulator of the NLRP3 inflammasome by mediating deubiquitination of NLRP3, leading to NLRP3 inflammasome assembly. Down-regulates the response to bacterial lipopolysaccharide (LPS) via its role in IFNAR1 deubiquitination. Deubiquitinates HDAC1 and PWWP2B leading to their stabilization.
• Tissue Specificity: Heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas. Aberrantly expressed in the vast majority of breast tumors.
• KEGG Pathway:
  Homologous recombi.tion (hsa03440)
  NOD-like receptor sig.ling pathway (hsa04621)
• Reactome Pathway:
  Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks (R-HSA-5693565)
  Nonhomologous End-Joining (NHEJ) (R-HSA-5693571)
  Processing of DNA double-strand break ends (R-HSA-5693607)
  G2/M DNA damage checkpoint (R-HSA-69473)
  Metalloprotease DUBs (R-HSA-5689901)

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[1]
Cervical cancer	DISFSHPF	Strong	Altered Expression	[2]
Cervical carcinoma	DIST4S00	Strong	Altered Expression	[2]
Childhood myelodysplastic syndrome	DISMN80I	Strong	Genetic Variation	[3]
Cytomegalovirus infection	DISCEMGC	Strong	Altered Expression	[4]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[1]
Glioma	DIS5RPEH	Strong	Biomarker	[1]
Myelodysplastic syndrome	DISYHNUI	Strong	Genetic Variation	[5]
Myelodysplastic/myeloproliferative neoplasm	DISDHXQ4	Strong	Biomarker	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]
Osteoporosis	DISF2JE0	Strong	Altered Expression	[6]
Parkinson disease	DISQVHKL	Strong	Altered Expression	[7]
Severe hemophilia A	DISXUFDW	Strong	Genetic Variation	[8]
Triple negative breast cancer	DISAMG6N	Strong	Genetic Variation	[9]
Vascular disease	DISVS67S	Strong	Genetic Variation	[10]
Venous thromboembolism	DISUR7CR	Strong	Genetic Variation	[11]
Nasopharyngeal carcinoma	DISAOTQ0	moderate	Altered Expression	[12]
Breast cancer	DIS7DPX1	Limited	Biomarker	[2]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[2]
Breast neoplasm	DISNGJLM	Limited	Altered Expression	[12]
Keratoconjunctivitis sicca	DISNOENH	Limited	Altered Expression	[13]
Moyamoya disease	DISO62CA	Limited	Autosomal dominant	[14]

15 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Lys-63-specific deubiquitinase BRCC36 (BRCC3).	[15]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Lys-63-specific deubiquitinase BRCC36 (BRCC3).	[16]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Lys-63-specific deubiquitinase BRCC36 (BRCC3).	[17]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Lys-63-specific deubiquitinase BRCC36 (BRCC3).	[18]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Lys-63-specific deubiquitinase BRCC36 (BRCC3).	[19]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Lys-63-specific deubiquitinase BRCC36 (BRCC3).	[20]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Lys-63-specific deubiquitinase BRCC36 (BRCC3).	[21]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Lys-63-specific deubiquitinase BRCC36 (BRCC3).	[22]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Lys-63-specific deubiquitinase BRCC36 (BRCC3).	[25]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Lys-63-specific deubiquitinase BRCC36 (BRCC3).	[26]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Lys-63-specific deubiquitinase BRCC36 (BRCC3).	[27]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Lys-63-specific deubiquitinase BRCC36 (BRCC3).	[28]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of Lys-63-specific deubiquitinase BRCC36 (BRCC3).	[29]
Rutin	DMEHRAJ	Investigative	Rutin decreases the expression of Lys-63-specific deubiquitinase BRCC36 (BRCC3).	[30]
CATECHIN	DMY38SB	Investigative	CATECHIN decreases the expression of Lys-63-specific deubiquitinase BRCC36 (BRCC3).	[30]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Lys-63-specific deubiquitinase BRCC36 (BRCC3).	[23]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Lys-63-specific deubiquitinase BRCC36 (BRCC3).	[24]

References

• [1] Downregulation of BRCA1-BRCA2-containing complex subunit 3 sensitizes glioma cells to temozolomide.Oncotarget. 2014 Nov 15;5(21):10901-15. doi: 10.18632/oncotarget.2543.
• [2] Knockdown of BRCC3 exerts an antitumor effect on cervical cancer invitro.Mol Med Rep. 2018 Dec;18(6):4886-4894. doi: 10.3892/mmr.2018.9511. Epub 2018 Sep 26.
• [3] BRCC3 mutations in myeloid neoplasms.Haematologica. 2015 Aug;100(8):1051-7. doi: 10.3324/haematol.2014.111989. Epub 2015 May 22.
• [4] Human cytomegalovirus-encoded miR-US25-1 aggravates the oxidised low density lipoprotein-induced apoptosis of endothelial cells.Biomed Res Int. 2014;2014:531979. doi: 10.1155/2014/531979. Epub 2014 May 8.
• [5] Functional characterization of BRCC3 mutations in acute myeloid leukemia with t(8;21)(q22;q22.1).Leukemia. 2020 Feb;34(2):404-415. doi: 10.1038/s41375-019-0578-6. Epub 2019 Oct 1.
• [6] Gene co-expression network analysis identifies BRCC3 as a key regulator in osteogenic differentiation of osteoblasts through a -catenin signaling dependent pathway.Iran J Basic Med Sci. 2019 Feb;22(2):173-178. doi: 10.22038/IJBMS.2018.29498.7123.
• [7] The BRCC3 regulated by Cdk5 promotes the activation of neuronal NLRP3 inflammasome in Parkinson's disease models.Biochem Biophys Res Commun. 2020 Feb 12;522(3):647-654. doi: 10.1016/j.bbrc.2019.11.141. Epub 2019 Nov 29.
• [8] Haemophilia A and cardiovascular morbidity in a female SHAM syndrome carrier due to skewed X chromosome inactivation.Eur J Med Genet. 2016 Jan;59(1):43-7. doi: 10.1016/j.ejmg.2015.12.004. Epub 2015 Dec 10.
• [9] Genetic evaluation of BRCA1 associated a complex genes with triple-negative breast cancer susceptibility in Chinese women.Oncotarget. 2016 Mar 1;7(9):9759-72. doi: 10.18632/oncotarget.7112.
• [10] Loss of BRCC3 deubiquitinating enzyme leads to abnormal angiogenesis and is associated with syndromic moyamoya.Am J Hum Genet. 2011 Jun 10;88(6):718-728. doi: 10.1016/j.ajhg.2011.04.017. Epub 2011 May 19.
• [11] Genome-wide association analysis of venous thromboembolism identifies new risk loci and genetic overlap with arterial vascular disease.Nat Genet. 2019 Nov;51(11):1574-1579. doi: 10.1038/s41588-019-0519-3. Epub 2019 Nov 1.
• [12] BRCC3 acts as a prognostic marker in nasopharyngeal carcinoma patients treated with radiotherapy and mediates radiation resistance in vitro.Radiat Oncol. 2015 May 30;10:123. doi: 10.1186/s13014-015-0427-3.
• [13] Mitochondrial DNA oxidation induces imbalanced activity of NLRP3/NLRP6 inflammasomes by activation of caspase-8 and BRCC36 in dry eye.J Autoimmun. 2017 Jun;80:65-76. doi: 10.1016/j.jaut.2017.02.006. Epub 2017 Feb 24.
• [14] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [15] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [16] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [17] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [18] Cannabidiol Modulates the Immunophenotype and Inhibits the Activation of the Inflammasome in Human Gingival Mesenchymal Stem Cells. Front Physiol. 2016 Nov 24;7:559. doi: 10.3389/fphys.2016.00559. eCollection 2016.
• [19] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [20] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [21] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [22] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [23] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [24] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [25] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [26] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [27] Expression and DNA methylation changes in human breast epithelial cells after bisphenol A exposure. Int J Oncol. 2012 Jul;41(1):369-77.
• [28] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [29] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.
• [30] Epicatechin and a cocoa polyphenolic extract modulate gene expression in human Caco-2 cells. J Nutr. 2004 Oct;134(10):2509-16.